Design and synthesis of malonic acid-based inhibitors of human neutrophil collagenase (MMP8).
For most of the known synthetic inhibitors of matrix metalloproteinases (MMPs), a substrate-like binding mode was postulated on the basis of X-ray crystallographic structures of MMP/inhibitor complexes. Conversely, the malonic acid-based inhibitor (2R,S)-HONH-CO-CH(i-Bu)-CO-Ala-Gly-NH2 was found to bind in a surprisingly different manner. Using this compound as a new lead structure, the interaction sites with human neutrophil collagenase (MMP8) were optimized with a series of iteratively designed analogues and with the help of X-ray structural analysis of selected inhibitors to finally produce low molecular weight nonpeptidic compounds of 500-1000-fold improved inhibitory potency.
Graf von Roedern
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E
Max-Planck-Institut für Biochemie, Martinsried, Germany.
Grams
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F
Brandstetter
H
H
Moroder
L
L
D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008314:Malonates / Q000737:chemistry*; D020784:Matrix Metalloproteinase 8; D061965:Matrix Metalloproteinase Inhibitors; D015394:Molecular Structure; D016339:Spectrometry, Mass, Fast Atom Bombardment
D004791:Enzyme Inhibitors; D008314:Malonates; D061965:Matrix Metalloproteinase Inhibitors; C030290:malonic acid; D020784:Matrix Metalloproteinase 8